Multiple system atrophy (MSA) is a progressive, degenerative neurological disorder, which is characterized clinically by the combination of varying degrees of Parkinsonism, autonomic dysfunction and impaired cerebellar function. The cardinal pathological feature of MSA is the presence of glial cytoplasmic inclusions (GCIs) in oligodendrocytes. Significant recent developments in the nascent research of MSA have been the development of consensus criteria for the clinical diagnosis of MSA and the discovery that a major component of GCIs is a-synuclein. Research in MSA has been hampered by the fact that MSA, though not rare, is not common enough for a single center to study a sufficient number of subjects and, until now, an absence of insights into molecules involved in the disorder. The focuses of the proposed work are to study pathogenic factors for MSA, particularly the role that alpha-synuclein plays, and to evaluate and refine clinical and laboratory assessments used to diagnose and follow the course of the illness. A central component of our effort will be recruitment and semiannual evaluation of a cohort of 175 clinically probable MSA subjects and evaluation 350 case control subjects. The clinical evaluations will be carried out at 11 sites and overseen by Core A (Administrative and Clinical) and Core B (Data). These groups of MSA and control subjects will be the basis for studies of environmental risk factors (Project 1) and the development of a brain bank by Core C (Neuropathology) and a DNA Repository by Core D (Genetics). A subgroup of the MSA subjects will be involved in studies of autonomic function in MSA (Project 4). Projects 2 and 3 will study the biology of a-synuclein in brains from MSA subjects acquired in Core C. Project 3 will utilize transgenic mice that overexpress g-synuclein to study factors that affect accumulation, aggregation and toxicity of a-synuclein in oligodendrocytes. The proposed program project is the first comprehensive study of a diagnostic tools and pathogenesis of MSA.